This laboratory studies the mechanisms by which the thyrotropin receptor (TSHR) regulates thyroid growth and function and the mechanisms by which self-tolerance is maintained during hormonally induced growth and function. We study the events which lead to the development of thyroid autoimmunity or tumors when these processes fail and the relationships of thyroid autoimmunity to other autoimmune diseases, i.e. diabetes and lupus. Improved diagnostic procedures and therapeutic modalities are pursued in these areas. With respect to autoimmunity, we have pursued our hypothesis that autoimmune thyroid disease, diabetes, SLE, and eye disease are initiated by a target tissue change in MHC gene expression, converting normal cells to antigen presenting cells. We have shown that altered antigen presentation associated with autoimmune disease of the thyroid may be induced not only by viral infection but also by the entrance of any ds polynucleotides <25 bp into the cytoplasm of target tissue cells. There is no sequence specificity, the phenomenon exists in a wide variety of cells, and can be induced by viral infection or tissue injury. The ds polynucleotides increase MHC gene expression, expression of genes important for antigen presentation (TAP, LMP2, Ii, HLA-DM, B7), and activation of signaling genes important in autoimmune processes (NF-kappaB, MAK, STAT1, STAT3). This induces bystander activation of immune cells. The mechanism is different from interferon (IFN) particularly with respect to CIITA and additive with IFN. This phenomenon is evident in tumor cells and results, we hypothesize, from a host defense mechanism to protect the organism of oncogene damage, i.e. is a means to kill tumor cells by our immune response system. In this respect, we have linked the ds polynucleitide action to the expression of the 90 kDa tumor-associated immunosuppressor which is both a marker of tumors and HIV infections, an inducer of MHC class I expression, and an activator of immune killer cells. We have shown that methimazole (MMI) derivatives which we developed can suppress these ds polynucleotide actions, as well as the actions of IFN, and will prevent the development of diabetes in the NOD mouse and SLE in the (NZBxNZW) model. Further we have identified one MMI-sensitive transcription factor which is regulated by IFN, the Y box protein YB-1 in humans or TSEP-1 in rats. A fall out of these studies has been the observations that the increase in MHC and antigen presenting genes can be used as a marker for RNA virus infection, i.e. hepatitis viruses. Thus formation of the ds replicate induces changes in these genes even without formation of viral partricles. Additionally, since some of the MMI derivatives inhibit this process and are antiviral, this may be a means to develop antiviral drugs. Finally, using the Graves' model we have shown that overexpression of MHC genes in the target tissue is essential to the development of stimulating autoantibodies in Graves' but not TSH binding inhibiting autoantibodies. With respect to regulation of thyroid function and growth, we have uncovered a novel role of follicular thyroglobulin (TG) as a feedback suppressor of thyroid-specific genes, TSH receptor, TG, thyroid peroxidase (TPO), and the sodium iodide symporter (NIS), and have shown this is due to the specific suppression of thyroid-specific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8. We have shown suppression involves the apical membrane TG receptor and that its expression can be regulated by TG autophosphorylation. Last we have shown that TTF-1 is present in previously unrecogniized non thyroid cells, i.e. C cells, parathyroid, anterior pituitary. The TTF-1 can act as a calcium sensor in C cells and regulates genes important for calcium homeostasis in C cells: calcitonin and the calcium sensing receptor. We hypothesize this phenomenon is important for the resynthesis of hormones and neurotropic factors whose release from cells is calcium dependent, including the release of pituitary hormones such as TSH, LH, and FSH. The calcium sensitivity of TTF-1 in the thyroid explains the basis for calcium down-regulation of the TSHR; this may influence thyroid hormone formation and secretion in certain disease states.